Chemical conjugates of evans blue derivatives and their use as radiotherapy and imaging agents

Patent metadata

Field	Value
Publication number	US-10696631-B2
Application number	US-201716099488-A
Country	US
Kind code	B2
Filing date	May 9, 2017
Priority date	May 9, 2016
Publication date	Jun 30, 2020
Grant date	Jun 30, 2020

Abstract

The present invention is directed to a compound of Formula I or Formula III or a pharmaceutically acceptable ester, amide, solvate, or salt thereof, or a salt of such an ester or amide or a solvate of such an ester amide or salt: wherein the definitions R 1 -R 13 and L 1 -L 4 are provided in the disclosure, and wherein R14 is a peptide. The compounds of Formula I may be covalently bonded to a peptide via a linker to provide a compound of Formula III and thereby extend the half-life of the therapeutic compound. The invention is also directed to pharmaceutical compositions of the disclosed compounds, as well as their use in the diagnosis or treatment of diseases.

First claim

What is claimed is:

1. A compound of Formula I or a pharmaceutically acceptable ester, amide, solvate, or salt thereof, or a salt of such an ester or amide or a solvate of such an ester amide or salt,

wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 5 , R 9 , R 10 , and R 11 are chosen independently from hydrogen, halogen, hydroxyl, cyano, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;
R 12 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
L 1 is (CH 2 ) m — wherein m is an integer from 0 to 12, wherein each CH 2 can be individually replaced with —O—, —NH(CO)—, or —(CO)—NH—, providing no two adjacent CH 2 groups are replaced;
L 2 is —(CH 2 ) m — wherein n is an integer from 0 to 12, wherein each CH 2 can be individually replaced with —O—, —NH(CO)—, or —(CO)—NH—, providing no two adjacent CH 2 groups are replaced;
L 3 is —(CH 2 ) p — wherein p is an integer from 0 to 12, wherein each CH 2 can be individually replaced with —O—, —NH(CO)—, or —(CO)—NH—, providing no two adjacent CH 2 groups are replaced; and
R 13 is a chelating group.

2. The compound of claim 1 , wherein L 1 is —NH(CO)—.

3. The compound of claim 1 , wherein L 2 is —(CH 2 ) 4 —NH(CO)—(CH 2 ) 2 —.

4. The compound of claim 1 , wherein L 3 is NH(CO)CH 2 —.

5. The compound of claim 1 , wherein R 1 and R 4 are chosen independently from halogen, hydroxyl, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.

6. The compound of claim 1 , wherein R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each hydrogen.

7. The compound of claim 5 , wherein R 1 and R 4 are chosen independently from C 1 -C 6 alkyl.

8. The compound of claim 7 , wherein R 1 and R 4 are each methyl.

9. The compound of claim 1 , wherein R 12 is hydrogen.

10. The compound of claim 1 , wherein R 13 is selected from

a crown ether, a cyclodextrin, or a porphyrin.

11. The compound of claim 1 , wherein the compound of Formula I is a compound of Formula II:

wherein:
L 2 is —(CH 2 ) n — wherein n is an integer from 0 to 12, wherein each CH 2 can be individually replaced with —O—, —NH(CO)—, or —(CO)—NH—, providing no two adjacent CH 2 groups are replaced; and
R 13 is a chelating group.

12. The compound of claim 11 , wherein L 2 is —(CH 2 ) 4 —NH(CO)—(CH 2 ) 2 —; and
R 13 is selected from

 a crown ether, a cyclodextrin, or a porphyrin.

13. A compound of Formula III or a pharmaceutically acceptable ester, amide, solvate, or salt thereof, or a salt of such an ester or amide or a solvate of such an ester amide or salt,

wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 5 , R 9 , R 10 , and R 11 are chosen independently from hydrogen, halogen, hydroxyl, cyano, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;
R 12 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 14 is a peptide;
L 1 is —(CH 2 ) m — wherein m is an integer from 0 to 12, wherein each CH 2 can be individually replaced with —O—, —NH(CO)—, or —(CO)—NH—, providing no two adjacent CH 2 groups are replaced;
L 2 is —(CH 2 ) n — wherein n is an integer from 0 to 12, wherein each CH 2 can be individually replaced with —O—, —NH(CO)—, or —(CO)—NH—, providing no two adjacent CH 2 groups are replaced;
L 3 is —(CH 2 ) p — wherein p is an integer from 0 to 12, wherein each CH 2 can be individually replaced with —O—, —NH(CO)—, or —(CO)—NH—, providing no two adjacent CH 2 groups are replaced; and
L 4 is —(CH 2 ) q — wherein q is an integer from 0 to 12, wherein each CH 2 can be individually replaced with —O—, —NH(CO)—, or —(CO)—NH—, providing no two adjacent CH 2 groups are replaced; and
R 13 is a chelating group.

14. The compound of claim 13 wherein L 1 is —NH(CO)—, R 1 and R 4 are each methyl, and R 2 , R 3 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are each hydrogen.

15. The compound of claim 13 , wherein R 14 is a therapeutic peptide.

16. The compound of claim 13 , wherein R 14 is a peptide capable of binding to a target cell or tissue.

17. The compound of claim 16 , wherein R 14 is capable of binding to a tumor.

18. The compound of claim 16 , wherein R 14 is selected from interferon alpha, GCSF, octreotate, bombesin, RGD, alpha-MSH, CTT1298, or aptamers.

19. The compound of claim 18 , wherein R 14 is the cyclic peptide Arg-Gly-Asp-Phe-Lys.

20. The compound of claim 16 wherein R 14 is

21. The compound of claim 16 , wherein R 14 further comprises a radionuclide.

22. The compound of claim 21 , wherein the radionuclide is 18 F, 76 Br, 124 I, 125 I, or 131 I.

23. The compound of claim 21 , wherein R 14 is

24. The compound of claim 13 , wherein R 13 is selected from

a crown ether, a cyclodextrin, or a porphyrin.

25. The compound of claim 13 , wherein R 13 further comprises a radionuclide.

26. The compound of claim 25 , wherein the radionuclide is 64 Cu, 67 Cu, 90 Y, 86 Y, 111 In, 186 Re, 188 Re, 89 Zr, 99 Tc, 153 Sm, 213 Bi, 225 Ac, or 223 Ra.

27. The compound of claim 13 , wherein the compound of Formula III is a compound of Formula IV:

wherein:
R 14 is a peptide;
L 2 is —(CH 2 ) n — wherein n is an integer from 0 to 12, wherein each CH 2 can be individually replaced with —O—, —NH(CO)—, or —(CO)—NH—, providing no two adjacent CH 2 groups are replaced;
L 4 is —(CH 2 ) q — wherein q is an integer from 0 to 12, wherein each CH 2 can be individually replaced with —O—, —NH(CO)—, or —(CO)—NH—, providing no two adjacent CH 2 groups are replaced; and
R 13 is a chelating group.

28. The compound of claim 27 , wherein R 14 is a peptide capable of binding to a target cell or tissue.

29. The compound of claim 28 , wherein R 10 is capable of binding to a tumor.

30. The compound of claim 27 , wherein R 14 is the cyclic peptide Arg-Gly-Asp-Phe-Lys.

31. The compound of claim 27 wherein R 14 is

32. The compound of claim 27 , wherein
L 2 is —(CH 2 ) 4 —NH(CO)—(CH 2 ) 2 —; and
L 4 -R 14 is

Assignees

• Us Health

Inventors

• Chen Xiaoyuan
• Jacobson Weiss Orit

Classifications

• C07D207/444

  having two doubly-bound oxygen atoms directly attached in positions 2 and 5 · CPC title

• A61K51/082

  the peptide being a RGD-containing peptide · CPC title

• A61K51/088

  conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10) · CPC title

• C09B29/30

  Amino naphtholsulfonic acid · CPC title

• C07D207/452 Primary

  with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom · CPC title